U.S. patent application number 10/394858 was filed with the patent office on 2003-10-02 for composition comprising 5-[4-[2-(n-methyl-n-2-pyridyl)amino)ethoxy]benzyl]t- hiazolidine-2,4-dione.
This patent application is currently assigned to SmithKline Beecham plc. Invention is credited to Granett, Jeffrey Roger, Patel, Jaikrishna, Price, Robin Kevin John, Ross, Hamish, Wray, Paul Nigel.
Application Number | 20030187030 10/394858 |
Document ID | / |
Family ID | 27268877 |
Filed Date | 2003-10-02 |
United States Patent
Application |
20030187030 |
Kind Code |
A1 |
Granett, Jeffrey Roger ; et
al. |
October 2, 2003 |
Composition comprising
5-[4-[2-(N-methyl-N-2-pyridyl)amino)ethoxy]benzyl]t-
hiazolidine-2,4-dione
Abstract
A pharmaceutical composition comprising Compound (I),
characterised in that the composition comprises 2 to 12 mg of
Compound (I) in a pharmaceutically acceptable form and optionally a
pharmaceutically acceptable carrier therefor, the use of such a
composition in medicine, processes for the preparation of such a
composition and intermediate composition useful in such a
process.
Inventors: |
Granett, Jeffrey Roger;
(Rosemont, PA) ; Ross, Hamish; (Berwyn, PA)
; Patel, Jaikrishna; (Research Triangle Park, NC)
; Price, Robin Kevin John; (Great Dunmow, GB) ;
Wray, Paul Nigel; (Crawley, GB) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham plc
Smith Kline Beecham Corporation
|
Family ID: |
27268877 |
Appl. No.: |
10/394858 |
Filed: |
March 21, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10394858 |
Mar 21, 2003 |
|
|
|
10068514 |
Feb 5, 2002 |
|
|
|
10068514 |
Feb 5, 2002 |
|
|
|
09424278 |
Mar 21, 2000 |
|
|
|
09424278 |
Mar 21, 2000 |
|
|
|
PCT/EP98/03478 |
Jun 2, 1998 |
|
|
|
Current U.S.
Class: |
514/342 |
Current CPC
Class: |
A61K 31/4439
20130101 |
Class at
Publication: |
514/342 |
International
Class: |
A61K 031/4439 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 5, 1997 |
GB |
9711683.4 |
Jun 18, 1997 |
GB |
9712851.6 |
Claims
1. A pharmaceutical composition comprising
5-[4-[2-(N-methyl-N-(2-pyridyl)-
amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter `Compound
(I)`), characterised in that the composition comprises 2 to 12 mg
of Compound (I) in a pharmaceutically acceptable form and
optionally a pharmaceutically acceptable carrier therefor.
2. A composition according to claim 1, which comprises 2 to 4 mg of
Compound (I) in a pharmaceutically acceptable form.
3. A composition according to claim 1, which comprises 4 to 8 mg of
Compound (I) in a pharmaceutically acceptable form.
4. A composition according to claim 1, which comprises 8 to 12 mg
of Compound (I) in a pharmaceutically acceptable form.
5. A composition according to claim 1, which comprises 2 mg of
Compound (I) in a pharmaceutically acceptable form.
6. A composition according to claim 1, which comprises 4 mg of
Compound (I) in a pharmaceutically acceptable form.
7. A composition according to claim 1, which comprises 8 mg of
Compound (I) in a pharmaceutically acceptable form.
8. A composition according to any one of claims 1 to 7, which
comprises the maleate salt of Compound (I)
9. A process for preparing a pharmaceutical composition comprising
2 to 12 mg of Compound (I) in a pharmaceutically acceptable form,
and a pharmaceutically acceptable carrier therefor, which process
comprises admixing 2 to 12 mg of Compound (I) in a pharmaceutically
acceptable form and the pharmaceutically acceptable carrier.
10. A process for preparing a pharmaceutical composition of
Compound (I) in a pharmaceutically acceptable form and a
pharmaceutically acceptable carrier, which process comprises: (i)
preparing a first composition comprising Compound (I) in a
pharmaceutically acceptable form and a first pharmaceutically
acceptable carrier; (ii) admixing the first composition with a
second pharmaceutically acceptable carrier to provide the required
composition of Compound (I) and optionally thereafter formulating
the composition produced into an administerable form.
11. A process according to claim 9 or claim 10, wherein the
composition prepared is in unit dosage form.
12. A process according to claim 9 or claim 10, wherein
the-composition prepared is a tablet.
13. A composition for use as a first composition in a process
according to claim 10, for preparing a unit dose of Compound (I) in
a pharmaceutically acceptable form.
14. A composition comprising Compound (I) in a pharmaceutically
acceptable form and optionally a pharmaceutically acceptable
carrier, characterised in that the composition is a
pharmaceutically acceptable, pre-administration composition.
15. A pre-administration composition according to claim 13, which
is a concentrate of Compound (I) in a pharmaceutically acceptable
form.
16. A composition comprising Compound (I) in a pharmaceutically
acceptable form and a pharmaceutically acceptable carrier,
characterised in that the composition is a concentrate of Compound
(I) in a pharmaceutically acceptable form, adapted to be diluted so
as to provide a composition for administration.
17. A composition according to any one of claims 13 to 16, which
contains up to 50% by weight of Compound (I) in a pharmaceutically
acceptable form.
18. A composition according to any one of claims 13 to 17, which
contains an amount of Compound (I) in a pharmaceutically acceptable
form in the range of from 5 to 20% by weight.
19. A composition according to any one of claims 13 to 18, which
contains 5%, 10% or 15% by weight of Compound (I) in a
pharmaceutically acceptable form.
20. A composition according to any one of claims 13 to 19, which
contains Compound (I) in a pharmaceutically acceptable form, sodium
starch glycollate, hydroxypropyl methylcellulose 2910,
microcrystalline cellulose and lactose monohydrate.
21. A composition according to any one of claims 13 to 20, in
granular form.
Description
[0001] This invention relates to a composition, in particular to a
pharmaceutical composition, and to the use of such a composition in
medicine, to processes for the preparation of such a composition
and to a composition useful in such a process.
[0002] European Patent Application, Publication Number 0,306,228
relates to certain thiazolidinedione derivatives disclosed as
having hypoglycaemic and hypolipidaemic activity. One particular
thiazolidinedione disclosed in EP 0306228 is
5-[4-[2-(N-methyl-N-(2-pyrid-
yl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter
`Compound (I)`). International Patent Application, publication
number WO94/05659 discloses certain salts of Compound (I),
including the maleate salt at Example 1 thereof.
[0003] It is now surprisingly indicated that a discrete and
particular daily dosage of Compound (I) provides an especially
beneficial effect on glycaemic control and is therefore
particularly useful for treatment of diabetes mellitus, especially
Type II diabetes and conditions associated with diabetes
mellitus.
[0004] We have also discovered a new and advantageous method for
preparing pharmaceutical compositions, especially unit dosage
compositions, containing Compound (I). The new method involves the
preparation of a pre-administration concentrate of Compound (I)
which thereafter is formulated into the required unit dose in an
efficient and economical manner. The new process is particularly
advantageous for the preparation of tablets of Compound (I).
[0005] Accordingly, in a first aspect the present invention
provides a pharmaceutical composition, suitably in unit dosage
form, comprising Compound (I), characterised in that the
composition comprises 2 to 12 mg of Compound (I) in a
pharmaceutically acceptable form and optionally a pharmaceutically
acceptable carrier therefor.
[0006] Suitable pharmaceutically acceptable forms of Compound (I)
include pharmaceutically acceptable salted forms and
pharmaceutically acceptable solvated forms, including
pharmaceutically acceptable solvated forms of pharmaceutically
acceptable salts.
[0007] Suitable compositions comprise 2, 3, 4, 5, 6, 7, 8, 9, 10,
11 or 12 mg of Compound (I) in a pharmaceutically acceptable
form.
[0008] Particular compositions comprise 2 to 4 mg of Compound (I)
in a pharmaceutically acceptable form.
[0009] Particular compositions comprise 4 to 8 mg of Compound (I)
in a pharmaceutically acceptable form.
[0010] Particular compositions comprise 8 to 12 mg of Compound (I)
in a pharmaceutically acceptable form.
[0011] One composition comprises 2 mg of Compound (I) in a
pharmaceutically acceptable form.
[0012] Preferred compositions comprise 4 mg of Compound (I) in a
pharmaceutically acceptable form.
[0013] Preferred compositions comprise 8 mg of Compound (I) in a
pharmaceutically acceptable form.
[0014] Suitable pharmaceutically acceptable salted forms of
Compound (I) include those described in EP 0306228 and WO94/05659.
A preferred pharmaceutically acceptable salt is a maleate.
[0015] Suitable pharmaceutically acceptable solvated forms of
Compound (I) include those described in EP 0306228 and WO94/05659,
in particular hydrates.
[0016] Compound (I) or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable solvate thereof, may be prepared
using known methods, for example those disclosed in EP 0306228 and
WO94/05659. The disclosures of EP 0306228 and WO94/05659 are
incorporated herein by reference.
[0017] Compound (I) may exist in one of several tautomeric forms,
all of which are encompassed by the term `Compound (I)` as
individual tautomeric forms or as mixtures thereof.
[0018] Compound (I) contains a chiral carbon atom, and hence can
exist in up to two stereoisomeric forms, the term Compound (I)
encompasses all of these isomeric forms whether as individual
isomers or as mixtures of isomers, including racemates.
[0019] When used herein the term `conditions associated with
diabetes` includes those conditions associated with the
pre-diabetic state, conditions associated with diabetes mellitus
itself and complications associated with diabetes mellitus.
[0020] When used herein the term `conditions associated with the
pre-diabetic state` includes conditions such as insulin resistance,
including hereditary insulin resistance, impaired glucose tolerance
and hyperinsulinaemia.
[0021] `Conditions associated with diabetes mellitus itself`
include hyperglycaemia insulin resistance, including acquired
insulin resistance and obesity. Further conditions associated with
diabetes mellitus itself include hypertension, cardiovascular
disease, especially atherosclerosis, certain eating disorders, in
particular those requiring the regulation of appetite and food
intake, such as disorders associated with under-eating, for example
anorexia nervosa and disorders associated with over-eating, for
example obesity and anorexia bulimia. Additional conditions
associated with diabetes mellitus itself include polycystic ovarian
syndrome and steroid induced insulin resistance and gestational
diabetes.
[0022] `Complications associated with diabetes mellitus` includes
renal disease, especially renal disease associated with Type II
diabetes, including diabetic nephropathy, glomerulonephritis,
glomerular sclerosis, nephrotic syndrome, hypertensive
nephrosclerosis and end stage renal disease.
[0023] As used herein the term `pharmaceutically acceptable`
embraces both human and veterinary use: for example the term
`pharmaceutically acceptable` embraces a veterinarily acceptable
compound.
[0024] As used herein the term concentrate with respect to Compound
(I) in a pharmaceutically acceptable form means a proportionate
amount of Compound (I) in a pharmaceutically acceptable form
greater than that present in an administerable composition.
[0025] For the avoidance of doubt, when reference is made herein to
scalar amounts, including mg amounts and % weight amounts, of
`Compound (I) in a pharmaceutically acceptable form`, the scalar
amount referred to is made in respect of Compound (I) per se: For
example 2 mg of Compound (I) in the form of the maleate salt is
that amount of maleate salt which contains 2 mg of Compound
(I).
[0026] Diabetes mellitus is preferably Type II diabetes.
[0027] In a further aspect, the invention provides a process for
preparing a pharmaceutical composition comprising 2 to 12 mg of
Compound (I) in a pharmaceutically acceptable form, and a
pharmaceutically acceptable carrier therefor, which process
comprises admixing 2 to 12 mg of Compound (I) in a pharmaceutically
acceptable form and the pharmaceutically acceptable carrier and
optionally thereafter formulating the composition produced into an
administerable form.
[0028] As indicated above the invention also provides a further
process for preparing a pharmaceutical composition comprising
Compound (I) in a pharmaceutically acceptable form which is
particularly suitable for preparing a range of unit dosage forms of
Compound (I). Accordingly, the invention further provides a process
for preparing a pharmaceutical composition of Compound (I) in a
pharmaceutically acceptable form and a pharmaceutically acceptable
carrier, which process comprises:
[0029] (i) preparing a first composition comprising Compound (I) in
a pharmaceutically acceptable form and a first pharmaceutically
acceptable carrier;
[0030] (ii) admixing the first composition with a second
pharmaceutically acceptable carrier to provide the required
composition of Compound (I) and optionally thereafter formulating
the composition produced into an administerable form.
[0031] A preferred administerable form of the pharmaceutical
composition of Compound (I) is a unit dose composition.
[0032] Unless otherwise specified, suitable unit doses comprise up
to 12 mg, such as 1 to 12 mg, of Compound (I) in a pharmaceutically
acceptable form.
[0033] Other unit doses include those mentioned herein.
[0034] A key component of the last above mentioned process is the
first composition. Accordingly, the present invention also provides
a composition for use as a first composition in a process for
preparing a unit dose of Compound (I) in a pharmaceutically
acceptable form.
[0035] The invention also provides a composition comprising
Compound (I) in a pharmaceutically acceptable form and optionally a
pharmaceutically acceptable carrier, characterised in that the
composition is a pharmaceutically acceptable, pre-administration
composition.
[0036] A suitable pharmaceutically acceptable, pre-administration
composition is a concentrate, preferably a granular concentrate, of
Compound (I) in a pharmaceutically acceptable form. The granular
concentrate is particularly well adapted to be diluted to provide a
composition for administration, preferably a tablet.
[0037] In a further aspect the invention provides a composition
comprising Compound (I) in a pharmaceutically acceptable form and a
pharmaceutically acceptable carrier, characterised in that the
composition is a concentrate of Compound (I) in a pharmaceutically
acceptable form, adapted to be diluted so as to provide a
composition for administration.
[0038] Suitably, the first composition, pre-administration
composition or dilutable composition (hereinafter referred to for
convenience as `the first composition`) contains up to 50% by
weight, for example an amount in the range of from 2 to 50% by
weight, of Compound (I) in a pharmaceutically acceptable form.
[0039] Favourably, the first composition contains an amount of
Compound (I) in a pharmaceutically acceptable form in the range of
from 5 to 20% by weight, in particular 5%, 10% or 15% by weight,
for example 10% by weight.
[0040] The processes of the invention can provide pharmaceutical
compositions of Compound (I) in any conventionally administerable
form, including orally or parenterally adminsterable forms. They
are particularly well adapted for preparing orally administrable
forms, especially tablet forms of Compound (I) in a
pharmaceutically acceptable form.
[0041] The first pharmaceutically acceptable carrier can comprise
any conventional pharmaceutically acceptable carrier comprising
conventional pharmaceutically acceptable excipients, including
those disclosed in the reference texts mentioned below. However, as
it is not essential that the first pharmaceutically acceptable
carrier is in an administerable form, then it need not contain
excipients solely associated with administration. For example the
first pharmaceutically acceptable carrier need not contain a
lubricant.
[0042] The second pharmaceutically acceptable carrier includes any
conventional pharmaceutically acceptable carrier comprising any
conventional pharmaceutically acceptable excipient, including
disintegrants, diluents and lubricants, including those disclosed
in the reference texts mentioned below.
[0043] One particular first composition comprises Compound (I) in a
pharmaceutically acceptable form, a disintegrant, a binder and a
diluent.
[0044] A suitable disintegrant is sodium starch glycollate.
[0045] A suitable binder is a methyl cellulose binder, such as
hydroxypropyl methylcellulose 2910.
[0046] Suitable diluents include cellulose, for example a
microcrystalline cellulose, and lactose monohydrate.
[0047] A suitable lubricant is magnesium stearate.
[0048] We have found that a particularly advantageous first
composition contains Compound (I) in a pharmaceutically acceptable
form, sodium starch glycollate, hydroxypropyl methylcellulose 2910,
microcrystalline cellulose and lactose monohydrate, especially when
in a granular form. This granular form has been found to be
particularly stable.
[0049] When the first composition contains about 10% by weight of
Compound (I) in a pharmaceutically acceptable form, it is readily
dilutable to give unit dose compositions comprising in the range of
between 2 to 12 mg, especially 2 to 8 mg, 2 to 4 mg, 4 to 8 mg and
8 to 12 mg of Compound (I) in a pharmaceutically acceptable
form.
[0050] The preparation of the first composition is suitably carried
using any conventional method appropriate to the nature of the said
first composition, for example wet granulation methods provide the
first composition in granular form.
[0051] Methods for formulating the compositions of the invention
into administerable forms include conventional formulation methods
as disclosed in the reference texts cited herein, including
tabletting methods.
[0052] The administerable compositions of the invention are
preferably adapted for oral administration. However, they may also
be adapted for other modes of administration, for example
parenteral administration, sublingual or transdermal
administration.
[0053] The administerable compositions may be in the form of
tablets, capsules, powders, granules, lozenges, suppositories,
reconstitutable powders, or liquid preparations, such as oral or
sterile parenteral solutions or suspensions.
[0054] In order to obtain consistency of administration it is
preferred that a composition of the invention is in the form of a
unit dose.
[0055] Unit dose presentation forms for oral administration may be
tablets and capsules and may contain conventional excipients such
as binding agents, for example syrup, acacia, gelatin, sorbitol,
tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,
sugar, maize-starch, calcium phosphate, sorbitol or glycine;
tabletting lubricants, for example magnesium stearate;
disintegrants, for example starch, polyvinylpyrrolidone, sodium
starch glycollate or microcrystalline cellulose; or
pharmaceutically acceptable wetting agents such as sodium lauryl
sulphate.
[0056] Unless otherwise prescribed, compositions of the invention
are preferably in unit dosage form in an amount appropriate for the
relevant daily dosage, suitable unit dosages comprise 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I) in a
pharmaceutically acceptable form.
[0057] The solid compositions for example the oral compositions may
be prepared by conventional methods of blending, filling or
tabletting. As required repeated blending operations may be used to
distribute the active agent throughout those compositions employing
large quantities of fillers. Such operations are of course
conventional in the art. The tablets may be coated according to
methods well known in normal pharmaceutical practice, in particular
with an aqueous film coating.
[0058] Liquid compositions, for example oral liquid compositions,
may be in the form of emulsions, syrups, or elixirs, or they may be
in a dry product form to be reconstituted with water or other
suitable vehicle before use. Such liquid preparations may contain
conventional additives such as suspending agents, for example
sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
carboxymethylcellulose, aluminium stearate gel, hydrogenated edible
fats; emulsifying agents, for example lecithin, sorbitan
monooleate, or acacia; non-aqueous vehicles (which may include
edible oils), for example almond oil, fractionated coconut oil,
oily esters such as esters of glycerine, propylene glycol, or ethyl
alcohol; preservatives, for example methyl or propyl
p-hydroxybenzoate or sorbic acid; and if desired conventional
flavouring or colouring agents.
[0059] Parenteral compositions, including parenteral administration
compositions for example unit dosage compositions, comprise the
active compound and a sterile vehicle, and, depending upon the
concentration used, can be either suspended or dissolved in the
vehicle. In preparing solutions for parenteral administration the
composition of the invention may be dissolved in water for
injection and filter sterilized before filling into a suitable vial
or ampoule and sealing. Advantageously, adjuvants such as a local
anaesthetic, a preservative and buffering agents can be dissolved
in the vehicle. To enhance the stability, the composition can be
frozen after filling into the vial and the water removed under
vacuum. Parenteral suspensions are prepared in substantially the
same manner, except that the active compound is suspended in the
vehicle instead of being dissolved, and sterilization cannot be
accomplished by filtration. The compound can be sterilized by
exposure to ethylene oxide before suspending in the sterile
vehicle. Advantageously, a surfactant or wetting agent is included
in the composition to facilitate uniform distribution of the
compound.
[0060] Unless otherwise specified the compositions of the invention
may contain from 0.1% to 99% by weight, preferably from 10-60% by
weight, of the active material, depending upon the method of
administration.
[0061] The composition may, if desired, be in the form of a pack
accompanied by written or printed instructions for use.
[0062] The compositions of the invention may be prepared and
formulated according to conventional methods, such as those
disclosed in standard reference texts, for example the British and
US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack
Publishing Co.), Martindale The Extra Pharmacopoeia (London, The
Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill
Books).
[0063] The present invention also provides a pharmaceutical
composition comprising 2 to 12 mg of Compound (I) and a
pharmaceutically acceptable carrier therefor, for use as an active
therapeutic substance.
[0064] In particular, the present invention provides a
pharmaceutical composition comprising 2 to 12 mg of Compound (I) in
a pharmaceutically acceptable form, for use in the treatment of
diabetes mellitus, especially Type II diabetes, and conditions
associated with diabetes mellitus.
[0065] The composition of the invention may be administered from 1
to 6 times a day, but most preferably 1 or 2 times per day.
[0066] Accordingly, in a further aspect the invention provides a
method for treatment of diabetes mellitus, especially Type II
diabetes and conditions associated with diabetes mellitus, in a
mammal such as a human, which method comprises administering per
day 2 to 12 mg of Compound (I) in a pharmaceutically acceptable
form, to a mammal in need thereof.
[0067] Particularly, the method comprises the administration of 2
to 4, 4 to 8 or 8 to 12 mg of Compound (I) in a pharmaceutically
acceptable form.
[0068] Particular dosages are 2 mg/day, 4 mg/day, including 2 mg
twice per day, and 8 mg/day, including 4 mg twice per day.
[0069] Particularly, the method comprises the administration of 2
to 4 mg of Compound (I) in a pharmaceutically acceptable form.
[0070] Particularly, the method comprises the administration of 4
to 8 mg of Compound (I) in a pharmaceutically acceptable form.
[0071] Particularly, the method comprises the administration of 8
to 12 mg of Compound (I) in a pharmaceutically acceptable form.
[0072] Preferably, the method comprises the administration of 2 mg
of Compound (I) in a pharmaceutically acceptable form.
[0073] Preferably, the method comprises the administration of 4 mg
of Compound (I) in a pharmaceutically acceptable form.
[0074] Preferably, the method comprises the administration of 8 mg
of Compound (I) in a pharmaceutically acceptable form.
[0075] A range of 2 to 4 mg includes a range of 2.1 to 4, 2.2 to 4,
2.3 to 4, 2.4 to 4, 2.5 to 4,2.6 to 4,2.7 to 4,2.8 to 4,2.9 to 4 or
3 to 4 mg.
[0076] A range of 4 to 8 mg includes a range of 4.1 to 8, 4.2 to 8,
4.3 to 8, 4.4 to 8,4.5 to 8,4.6 to 8,4.7 to 8,4.8 to 8,4.9 to 8, 5
to 8,6 to 8 or 7 to 8 mg.
[0077] A range of 8 to 12 mg includes a range of 8.1 to 12, 8.2 to
12, 8.3 to 12, 8.4 to 12, 8.5 to 12,8.6 to 12,8.7 to 12,8.8 to
12,8.9 to 12,9 to 12, 10 to 12 or 11 to 12 mg.
[0078] No adverse toxicological effects have been established for
the compositions or methods of the invention in the abovementioned
dosage ranges.
[0079] The following examples illustrate the invention but do not
limit it in any way.
EXAMPLE 1
Concentrate Preparation
[0080] Approximately two thirds of the lactose monohydrate is
passed through a suitable screen and blended with the milled
maleate salt of Compound (I). Sodium starch glycollate,
hydoxypropyl methylcellulose, microcrystalline cellulose and the
remaining lactose are passed through a suitable screen and added to
the mixture. Blending is then continued. The resulting mixture is
then wet granulated with purified water. The wet granules are then
screened, dried on a fluid bed drier and the dried granules are
passed through a further screen and finally homogenised.
1 % COMPOSITION OF GRANULAR CONCENTRATE Ingredient Quantity (%)
Milled Compound (I) as maleate salt 13.25 (pure maleate salt)
Sodium Starch Glycollate 5.00 Hydoxypropyl Methylcellulose 2910
5.00 Microcrystalline Cellulose 20.0 Lactose Monohydrate, regular
grade to 100 Purified water * *Removed during processing.
EXAMPLE 2
Formulation of the Concentrate Into Tablets
[0081] The granules from Example 1 are placed into a tumble
blender. Approximately two thirds of the lactose is screened and
added to the blender. The microcrystalline cellulose, sodium starch
glycollate, magnesium stearate and remaining lactose are screened
and added to the blender and the mixture blended together. The
resulting mix is then compressed on a rotary tablet press to a
target weight of 150 mg for the 1, 2 and 4 mg tablets and to a
target weight of 300 mg for the 8 mg tablets. The tablet cores are
then transferred to a tablet coating machine, pre-warmed with warm
air (approximately 65.degree. C.) and film coated until the tablet
weight has increased by 2.0% to 3.5%.
2 Quantity (mg per Tablet) Tablet Strength 1.0 mg 2.0 mg 4.0 mg 8.0
mg Active Ingredient: Compound (I) malcate Concentrate 10.00 20.00
40.00 80.00 granules Other Ingredients: Sodium Starch Glycollate
6.96 6.46 5.46 10.92 Microcrystalline Cellulose 27.85 25.85 21.85
43.70 Lactose monohydrate 104.44 96.94 81.94 163.88 Magnesium
Stearate 0.75 0.75 0.75 1.50 Total Weight of Tablet Core 150.0
150.0 150.0 300.0 Aqueous film coating material 4.5 4.5 4.5 9.0
Total Weight of Film Coated 154.5 154.5 154.5 309.0 Tablet
* * * * *